What are the pathophysiological mechanisms of preeclampsia (pre-eclampsia)?

From the Guidelines

Preeclampsia is a pregnancy complication characterized by new-onset hypertension and proteinuria, resulting from abnormal placentation, placental ischemia, and oxidative stress, which triggers the release of anti-angiogenic factors, leading to endothelial dysfunction and clinical manifestations. The primary mechanism involves abnormal placentation, where trophoblast cells fail to adequately invade and remodel maternal spiral arteries, leading to placental ischemia and oxidative stress 1. This placental dysfunction triggers the release of anti-angiogenic factors like soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng), which antagonize vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) 1. The resulting endothelial dysfunction affects multiple organ systems, causing widespread vasoconstriction, increased vascular permeability, and activation of inflammatory and coagulation cascades.

Some key points to consider in the mechanisms of preeclampsia include:

• Abnormal placentation and placental ischemia
• Release of anti-angiogenic factors
• Endothelial dysfunction
• Activation of inflammatory and coagulation cascades
• Maternal immune maladaptation to fetal antigens, genetic predisposition, and pre-existing conditions like chronic hypertension or diabetes also contribute to preeclampsia development 1.

The clinical manifestations of preeclampsia include hypertension, proteinuria, edema, and potential complications like HELLP syndrome (hemolysis, elevated liver enzymes, low platelets), eclampsia (seizures), and placental abruption 1. The only definitive treatment is delivery of the placenta, though antihypertensive medications like labetalol or nifedipine and magnesium sulfate for seizure prophylaxis are used to manage symptoms and prevent complications.

In terms of the renin-angiotensin-aldosterone system (RAAS) and its contributions to preeclampsia development and progression, the evidence suggests that RAAS dysregulation is a complex and multifactorial process, involving both the maternal and fetal compartments 1. The precise timing and importance of RAAS changes in preeclampsia remain unknown, and further research is needed to elucidate the role of RAAS in the pathophysiology of preeclampsia.

Overall, preeclampsia is a complex and multifactorial disorder, and a comprehensive understanding of its mechanisms and clinical manifestations is essential for the development of effective prevention and treatment strategies.

From the Research

Mechanisms of Pre-eclampsia

• Pre-eclampsia is a complex condition involving multiple pathophysiological factors, including vasospasm onset, coagulation system activation, increased inflammatory response, and ischemia 2
• The condition is characterized by the presence of maternal compromise or eclampsia, and the diagnosis of pre-eclampsia beyond the gestation period of 38 weeks requires delivery 2
• Several risk factors contribute to the development of pre-eclampsia, including microvascular diseases, vascular and connective tissue disorders, hypertension, antiphospholipid antibody syndrome, and nephropathy 2

Treatment of Pre-eclampsia

• Magnesium sulfate is the gold standard for the management of pre-eclampsia, but it has a short action time that does not provide stable maintenance of blood pressure 3
• Labetalol is currently recommended as first-line treatment by the national UK guidance, and it has been shown to provide proper reduction of blood pressure in Han Chinese women with pre-eclampsia 3
• However, labetalol has the risk of undesirable maternal and neonatal adverse effects, such as tachycardia, bradycardia, and intracranial hemorrhage in pregnant women, and respiratory distress syndrome and hypoglycemia in neonates 3
• Magnesium sulfate combined with nifedipine and labetalol has good efficacy in the treatment of pre-eclampsia, and can promote the expression of endogenous kallikrein, reduce the level of pregnancy-related hypertension predictors, and weaken the infiltration ability of cytotrophoblasts 4

Pharmacokinetics of Magnesium Sulfate

• Magnesium sulfate is usually given by either the intramuscular or intravenous routes, and the intravenous regimen is given as a 4 g dose, followed by a maintenance infusion of 1 to 2 g/h by controlled infusion pump 5
• After administration, about 40% of plasma magnesium is protein bound, and the unbound magnesium ion diffuses into the extravascular-extracellular space, into bone, and across the placenta and fetal membranes and into the fetus and amniotic fluid 5
• Magnesium is almost exclusively excreted in the urine, with 90% of the dose excreted during the first 24 hours after an intravenous infusion of MgSO4 5

Biomarkers for Pre-eclampsia

• Soluble fms-like tyrosine kinase-1 (sFlT-1) and placental growth factor (PlGF) are potential biomarkers for pre-eclampsia, and the sFlT-1/PlGF ratio has been shown to have a certain predictive value for the efficacy of early-onset severe pre-eclampsia treatment 6
• Magnesium sulfate combined with labetalol can improve the balance of sFlT-1 and PlGF, and decrease the sFlT-1/PlGF ratio, which may be beneficial for the treatment of pre-eclampsia 6